RESUMEN
Dysregulation of inflammation can lead to multiple chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Interleukin-6 (IL6) is crucial in regulating the inflammatory cascade, but the causal link between IL6 signaling downregulation and respiratory diseases risk is unclear. This study uses Mendelian randomization to examine the effects of IL6R blockade on respiratory diseases. Analyzing data from 522,681 Europeans, 26 genetic variants were obtained to mimic IL6R inhibition. Our findings show that IL6R blockade significantly reduces the risk of COPD (OR = 0.71, 95% CI = 0.60-9.84) and asthma (OR = 0.82, 95% CI = 0.74-0.90), with protective trends for bronchitis, pulmonary embolism, and lung cancer. Results were consistent across methods, with no significant heterogeneity or pleiotropy. These insights suggest IL6R downregulation as a potential therapeutic target for respiratory diseases, meriting further clinical investigation.
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Receptores de Interleucina-6 , Transducción de Señal , Humanos , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/metabolismo , Transducción de Señal/genética , Predisposición Genética a la Enfermedad , Factores de Riesgo , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Análisis de la Aleatorización Mendeliana , Enfermedades Respiratorias/genética , Enfermedades Respiratorias/metabolismo , Asma/genética , Trastornos Respiratorios/genéticaRESUMEN
Respiratory disorders are among the conditions that affect the respiratory system. The healthcare sector faces challenges due to the emergence of drug resistance to prescribed medications for these illnesses. However, there is a technology called CRISPR/Cas9, which uses RNA to guide DNA targeting. This technology has revolutionized our ability to manipulate and visualize the genome, leading to advancements in research and treatment development. It can effectively reverse epigenetic alterations that contribute to drug resistance. Some studies focused on health have shown that targeting genes using CRISPR/Cas9 can be challenging when it comes to reducing drug resistance in patients with respiratory disorders. Nevertheless, it is important to acknowledge the limitations of this technology, such as off-target effects, immune system reactions to Cas9, and challenges associated with delivery methods. Despite these limitations, this review aims to provide knowledge about CRISPR/Cas9 genome editing tools and explore how they can help overcome resistance in patients with respiratory disorders. Additionally, this study discusses concerns related to applications of CRISPR and provides an overview of successful clinical trial studies.
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Sistemas CRISPR-Cas , Edición Génica , Humanos , Edición Génica/métodos , Sistemas CRISPR-Cas/genética , Resistencia a Medicamentos/genética , Animales , Trastornos Respiratorios/genética , Trastornos Respiratorios/terapia , Trastornos Respiratorios/tratamiento farmacológico , Enfermedades Respiratorias/genética , Enfermedades Respiratorias/tratamiento farmacológico , Enfermedades Respiratorias/terapiaRESUMEN
Centronuclear myopathy (CNM) is a heterogeneous group of muscle disorders primarily characterized by muscle weakness and variable degrees of respiratory dysfunction caused by mutations in MTM1, DNM2, RYR1, TTN and BIN1. X-linked myotubular myopathy has been the focus of recent natural history studies and clinical trials. Data on respiratory function for other genotypes is limited. To better understand the respiratory properties of the CNM spectrum, we performed a retrospective study in a non-selective Dutch CNM cohort. Respiratory dysfunction was defined as an FVC below 70% of predicted and/or a daytime pCO2 higher than 6 kPa. We collected results of other pulmonary function values (FEV1/FVC ratio) and treatment data from the home mechanical ventilation centres. Sixty-one CNM patients were included. Symptoms of respiratory weakness were reported by 15/47 (32%) patients. Thirty-three individuals (54%) with different genotypes except autosomal dominant (AD)-BIN1-related CNM showed respiratory dysfunction. Spirometry showed decreased FVC, FEV1 & PEF values in all but two patients. Sixteen patients were using HMV (26%), thirteen of them only during night-time. In conclusion, this study provides insight into the prevalence of respiratory symptoms in four genetic forms of CNM in the Netherlands and offers the basis for future natural history studies.
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Miopatías Estructurales Congénitas , Trastornos Respiratorios , Humanos , Músculo Esquelético , Estudios Retrospectivos , Países Bajos/epidemiología , Dinamina II/genética , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/diagnóstico , Mutación , Trastornos Respiratorios/genéticaRESUMEN
Rett syndrome is a neurological disease due to loss-of-function mutations in the transcription factor, Methyl CpG binding protein 2 (MECP2). Because overexpression of endogenous MECP2 also causes disease, we have exploited a targeted RNA-editing approach to repair patient mutations where levels of MECP2 protein will never exceed endogenous levels. Here, we have constructed adeno-associated viruses coexpressing a bioengineered wild-type ADAR2 catalytic domain (Editasewt) and either Mecp2-targeting or nontargeting gfp RNA guides. The viruses are introduced systemically into male mice containing a guanosine to adenosine mutation that eliminates MeCP2 protein and causes classic Rett syndrome in humans. We find that in the mutant mice injected with the Mecp2-targeting virus, the brainstem exhibits the highest RNA-editing frequency compared to other brain regions. The efficiency is sufficient to rescue MeCP2 expression and function in the brainstem of mice expressing the Mecp2-targeting virus. Correspondingly, we find that abnormal Rett-like respiratory patterns are alleviated, and survival is prolonged, compared to mice injected with the control gfp guide virus. The levels of RNA editing among most brain regions corresponds to the distribution of guide RNA rather than Editasewt. Our results provide evidence that a targeted RNA-editing approach can alleviate a hallmark symptom in a mouse model of human disease.
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Tronco Encefálico , Proteína 2 de Unión a Metil-CpG , Edición de ARN , Trastornos Respiratorios , Síndrome de Rett , Animales , Tronco Encefálico/metabolismo , Modelos Animales de Enfermedad , Humanos , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Mutación , Trastornos Respiratorios/genética , Trastornos Respiratorios/terapia , Síndrome de Rett/genética , Síndrome de Rett/terapiaRESUMEN
INTRODUCTION: Methyl-CpG binding protein 2 gene (MECP2) is located on the X chromosome (Xq28) and is important for nervous and immune system functioning. Patients with MECP2 duplication syndrome (MDS) have recurrent respiratory infections (RRIs). Although RRIs often occur with MDS because some patients with MDS also have hypoimmunoglobulinemia and duplication of the interleukin-1-receptor-associated kinase-1 gene (IRAK1), which is also located on Xq28, the phenotype of IRAK1 duplication in patients with MDS remains unclear. METHODS: The clinical course of three patients with MDS who underwent laryngotracheal separation (LTS) at two institutions was summarized. RESULTS: Three patients with MDS were identified to have recurrent pneumonia characteristic of aspiration pneumonia, sometimes requiring artificial ventilation therapy; they had no other bacterial infections. After LTS, they rarely had pneumonia. In MDS, MECP2 expression increased two-fold naturally, while IRAK-1 expression showed no difference compared with a healthy subject. CONCLUSIONS: Since RRIs in MDS are thought to be caused by aspiration and not susceptibility to infection previously estimated to be major complication, the evaluation of aspiration is recommended for RRIs for better management of MDS.
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Discapacidad Intelectual Ligada al Cromosoma X , Neumonía , Trastornos Respiratorios , Duplicación de Gen , Humanos , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Fenotipo , Neumonía/complicaciones , Neumonía/genética , Trastornos Respiratorios/genéticaRESUMEN
We studied 33 patients affected by juvenile and adult myotonic dystrophy type 1 (DM1). The aim of the study was to assess clinical and laboratory parameters that could predict the requirement of noninvasive ventilation (NIV) in DM1. Secondary outcome was to assess the interplay between genetic profile, muscle impairment severity and presence of cardiac comorbidities.Patients with genetic diagnosis of DM1 were recruited. An abnormal trinucleotide repeat (CTG) expansion of dystrophy protein kinase gene (DMPK) on chromosome 19q13.3 was the prerequisite for inclusion. The number of triplet repeats was measured in genomic DNA to classify subjects. A multidisciplinary team evaluated the patients every 6-8 months up to 18 years with serial cardiological and respiratory function assessments. Neurological progression was monitored using a validated DM1-specific rating scale (MIRS). Independent variables considered for the study outcomes were gender, genetic status, age of presentation, MIRS scores, and results of pulmonary function tests (PFTs).Patients were 17 males (51.5%) and 16 females (48.5%). 16 cases were younger than mean age of 31.4 years, the remaining 17 were up to 65. 12 subjects (36.4%) underwent NIV during follow up. Cardiac comorbidities were detected in 63.6% of cases and in 91% of patients in NIV. Among PFTs, forced vital capacity (FVC) was a reliable indicator of respiratory decline. FVC values were significantly associated with clinical muscle severity assessed by MIRS.Severity of muscular impairment, CTG expansion size, age and presence of cardiac comorbidities predict respiratory impairment in DM1.
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Distrofia Miotónica/diagnóstico , Distrofia Miotónica/genética , Trastornos Respiratorios/diagnóstico , Trastornos Respiratorios/genética , Repeticiones de Trinucleótidos/genética , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Distrofia Miotónica/epidemiología , Valor Predictivo de las Pruebas , Trastornos Respiratorios/epidemiología , Pruebas de Función Respiratoria/tendencias , Adulto JovenRESUMEN
The lower airways (larynx to alveoli) are protected by a complex array of neural networks that regulate respiration and airway function. Harmful stimuli trigger defensive responses such as apnea, cough and bronchospasm by activating a subpopulation of sensory afferent nerves (termed nociceptors) which are found throughout the airways. Airway nociceptive fibers are projected from the nodose vagal ganglia, the jugular vagal ganglia and the dorsal root ganglia, which are derived from distinct embryological sources: the former from the epibranchial placodes, the latter two from the neural crest. Embryological source determines nociceptive gene expression of receptors and neurotransmitters and recent evidence suggests that placode- and neural crest-derived nociceptors have distinct stimuli sensitivity, innervation patterns and functions. Improved understanding of the function of each subset in specific reflexes has substantial implications for therapeutic targeting of the neuronal components of airway disease such as asthma, viral infections and chronic obstructive pulmonary disease.
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Pulmón/anatomía & histología , Pulmón/fisiología , Biología Molecular/métodos , Cresta Neural/anatomía & histología , Cresta Neural/fisiología , Nociceptores/fisiología , Animales , Expresión Génica , Humanos , Trastornos Respiratorios/genética , Trastornos Respiratorios/metabolismoRESUMEN
BACKGROUND: Chronic respiratory diseases have become a non-negligible cause of death globally. Although smoking and environmental exposures are primary risk factors for chronic respiratory diseases, genetic factors also play an important role in determining individual's susceptibility to diseases. Here we performed integrated gene-based and pathway analyses to systematically illuminate the heritable characteristics of chronic respiratory diseases. METHODS: UK (United Kingdom) Biobank is a very large, population-based prospective study with over 500,000 participants, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases. Utilizing the GWAS-summarized data downloaded from UK Biobank, we conducted gene-based analysis to obtain associations of susceptibility genes with asthma, chronic obstructive pulmonary disease(COPD) and pneumonia using FUSION and MAGMA software. Across the identified susceptibility regions, functional annotation integrating multiple functional data sources was performed to explore potential regulatory mechanisms with INQUISIT algorithm. To further detect the biological process involved in the development of chronic respiratory diseases, we undertook pathway enrichment analysis with the R package (clusterProfiler). RESULTS: A total of 195 susceptibility genes were identified significantly associated with chronic respiratory diseases (Pbonferroni < 0.05), and 24/195 located out of known susceptibility regions (e.g. WDPCP in 2p15). Within the identified susceptibility regions, functional annotation revealed an aggregation of credible variants in promoter-like and enhancer-like histone modification regions and such regulatory mechanisms were specific to lung tissues. Furthermore, 110 genes with INQUISIT score ≥1 may influence diseases susceptibility through exerting effects on coding sequences, proximal promoter and distal enhancer regulations. Pathway enrichment results showed that these genes were enriched in immune-related processes and nicotinic acetylcholine receptors pathways. CONCLUSIONS: This study implemented an integrated gene-based and pathway strategy to explore the underlying biological mechanisms and our findings may serve as promising targets for future clinical treatments of chronic respiratory diseases.
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Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Trastornos Respiratorios/genética , Asma/genética , Bancos de Muestras Biológicas , Enfermedad Crónica/epidemiología , Bases de Datos Genéticas , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/genética , Fumar/genética , Reino UnidoRESUMEN
Oseltamivir, a pro-drug, is the best option for treatment and chemoprophylaxis for influenza outbreaks. However, many patients treated with oseltamivir developed adverse reactions, including hypersensitivity, gastritis, and neurological symptoms. The aim of this study was to determine the adverse drug reactions (ADRs) in Mexican patients treated with oseltamivir and whether these ADRs are associated with SNPs of the genes involved in the metabolism, transport, and interactions of oseltamivir. This study recruited 310 Mexican patients with acute respiratory diseases and treated them with oseltamivir (75 mg/day for 5 days) because they were suspected to have influenza A/H1N1 virus infection. Clinical data were obtained from medical records and interviews. Genotyping was performed using real-time polymerase chain reaction and TaqMan probes. The association was assessed under genetic models with contingency tables and logistic regression analysis. Out of 310 patients, only 38 (12.25%) presented ADRs to oseltamivir: hypersensitivity (1.9%), gastritis (10%), and depression and anxiety (0.9%). The polymorphism ABCB1-rs1045642 was associated with adverse drug reactions under the recessive model (P = 0.017); allele C was associated with no adverse drug reactions, while allele T was associated with adverse drug reactions. The polymorphisms SLC15A1-rs2297322, ABCB1-rs2032582, and CES1-rs2307243 were not consistent with Hardy-Weinberg equilibrium, and no other associations were found for the remaining polymorphisms. In conclusion, the polymorphism rs1045642 in the transporter encoded by the ABCB1 gene is a potential predictive biomarker of ADRs in oseltamivir treatment.
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Antivirales/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Oseltamivir/metabolismo , Polimorfismo de Nucleótido Simple/genética , Trastornos Respiratorios/genética , Trastornos Respiratorios/metabolismo , Enfermedad Aguda , Adolescente , Adulto , Antivirales/efectos adversos , Transporte Biológico/fisiología , Niño , Interacciones Farmacológicas/fisiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Estudios de Asociación Genética/métodos , Humanos , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/tratamiento farmacológico , Gripe Humana/epidemiología , Gripe Humana/genética , Gripe Humana/metabolismo , Masculino , México/epidemiología , Persona de Mediana Edad , Oseltamivir/efectos adversos , Transporte de Proteínas/fisiología , Trastornos Respiratorios/tratamiento farmacológico , Trastornos Respiratorios/epidemiología , Estudios Retrospectivos , Adulto JovenRESUMEN
Circular RNAs (CircRNAs), as a new class of non-coding RNA molecules that, unlike linear RNAs, have covalently closed loop structures from the ligation of exons, introns, or both. CircRNAs are widely expressed in various organisms in a specie-, tissue-, disease- and developmental stage-specific manner, and have been demonstrated to play a vital role in the pathogenesis and progression of human diseases. An increasing number of recent studies has revealed that circRNAs are intensively associated with different respiratory diseases, including lung cancer, acute respiratory distress syndrome, pulmonary hypertension, pulmonary tuberculosis, and silicosis. However, to the best of our knowledge, there has been no systematic review of studies on the role of circRNAs in respiratory diseases. In this review, we elaborate on the biogenesis, functions, and identification of circRNAs and focus particularly on the potential implications of circRNAs in respiratory diseases.
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ARN/genética , ARN/metabolismo , Trastornos Respiratorios/genética , Trastornos Respiratorios/metabolismo , Animales , Humanos , Empalme del ARN/fisiología , ARN Circular , Trastornos Respiratorios/diagnósticoRESUMEN
Immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) mutations are associated with partial continuum between two extremes of rapidly lethal disorder of spinal muscular atrophy with respiratory distress type 1 (SMARD1), with infantile axonal neuropathy, diaphragmatic weakness and commonly death before 1 year of age, and Charcot-Marie-Tooth disease (CMT) type 2S with slowly progressive weakness and sensory loss but no significant respiratory compromise. We present an atypical case of CMT2S. A 9 month old boy presented with bilateral feet deformities and axonal neuropathy. Genetic testing revealed two heterozygous variants in the IGHMBP2 gene: c.1156 Tâ¯>â¯C p.(Trp386Arg) in exon 8 and c.2747Gâ¯>â¯A p.(Cys916Tyr) in exon 14, that were inherited from his father and mother respectively. At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition.
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Enfermedad de Charcot-Marie-Tooth/diagnóstico , Proteínas de Unión al ADN/genética , Diafragma/fisiopatología , Trastornos Respiratorios/diagnóstico , Factores de Transcripción/genética , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Niño , Preescolar , Humanos , Lactante , Masculino , Mutación , Trastornos Respiratorios/genética , Trastornos Respiratorios/fisiopatologíaRESUMEN
One of the epigenetic-modifying factors is regular and continuous physical activity. This article attempts to investigate the effects of physical activity and exercise on changes in histone proteins and gene expression, as well as the effect of these exercises on the prevention of certain cancers and the ejection of age-related illnesses and cellular oxidation interactions. All of this is due to epigenetic changes and gene expression. Most studies have reported the positive effects of regular exercises on the expression of histone proteins. DNA methylation and the prevention of certain diseases such as cancer and respiratory diseases, caused by antioxidative interactions that occur more often in the elderly, have been studied.
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Epigénesis Genética/genética , Ejercicio Físico , Histonas/genética , Neoplasias/genética , Metilación de ADN/genética , Humanos , Trastornos Respiratorios/genéticaRESUMEN
Purpose/aim of the study: To summarize recent studies on the pathophysiology and preventive strategies for SUDEP. Materials and methods: Databases and literature review. Results: Patients with epilepsy have a significantly higher risk of death than the general population. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of sudden death among patients with epilepsy. Despite on-going research, there are still deficits in our knowledge about the mechanisms, genetic factors, and prevention of SUDEP. Current evidence suggests that cardiac arrhythmias, respiratory dysfunction, and brainstem arousal system dysfunction are the major mechanisms of SUDEP, and animal models support the role of neurotransmitters, especially serotonin and adenosine, in pathophysiology of SUDEP. Several mutations in the neurocardiogenic channelopathy genes have been identified as a possible cause of epilepsy and increased SUDEP risk. The lack of awareness that SUDEP can be a potential cause of premature death has been found in several surveys. In addition, medical legal cases demonstrate the need for more education about this condition. Several preventive strategies to reduce SUDEP have been proposed, including effective seizure control, nocturnal supervision, seizure monitoring, devices to protect the airway, and selective serotonin reuptake inhibitors. Further research is needed to determine the efficacy of these interventions. Conclusions: The major mechanisms of SUDEP include cardiac arrhythmias, respiratory dysfunction, and brainstem arousal system dysfunction. Effective control of seizures is the only effective strategy to prevent SUDEP. Other preventive interventions require more research.
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Muerte Súbita/epidemiología , Muerte Súbita/prevención & control , Epilepsia/mortalidad , Epilepsia/terapia , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Epilepsia/epidemiología , Epilepsia/genética , Humanos , Mutación/genética , Trastornos Respiratorios/epidemiología , Trastornos Respiratorios/genética , Trastornos Respiratorios/mortalidad , Trastornos Respiratorios/terapia , Factores de RiesgoRESUMEN
Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, is associated with a peculiar breathing disturbance exclusively during wakefulness that is distressing, and can even prompt emergency resuscitation. Through the RTT Natural History Study, we characterized cross sectional and longitudinal characteristics of awake breathing abnormalities in RTT and identified associated clinical features. Participants were recruited from 2006 to 2015, and cumulative lifetime prevalence of breathing dysfunction was determined using the Kaplan-Meier estimator. Risk factors were assessed using logistic regression. Of 1205 participants, 1185 had sufficient data for analysis, including 922 females with classic RTT, 778 of whom were followed longitudinally for up to 9.0â¯years, for a total of 3944 person-years. Participants with classic or atypical severe RTT were more likely to have breathing dysfunction (nearly 100% over the lifespan) compared to those with atypical mild RTT (60-70%). Remission was common, lasting 1â¯year on average, with 15% ending the study in terminal remission. Factors associated with higher odds of severe breathing dysfunction included poor gross and fine motor function, frequency of stereotypical hand movements, seizure frequency, prolonged corrected QT interval on EKG, and two quality of life metrics: caregiver concern about physical health and contracting illness. Factors associated with lower prevalence of severe breathing dysfunction included higher body mass index and head circumference Z-scores, advanced age, and severe scoliosis or contractures. Awake breathing dysfunction is common in RTT, more so than seizures, and is associated with function, quality of life and risk for cardiac dysrhythmia.
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Trastornos Respiratorios/fisiopatología , Síndrome de Rett/fisiopatología , Adulto , Factores de Edad , Anciano , Índice de Masa Corporal , Niño , Preescolar , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Prevalencia , Calidad de Vida , Trastornos Respiratorios/epidemiología , Trastornos Respiratorios/etiología , Trastornos Respiratorios/genética , Síndrome de Rett/complicaciones , Síndrome de Rett/epidemiología , Síndrome de Rett/genética , Factores de Riesgo , Escoliosis/complicaciones , Escoliosis/epidemiología , Escoliosis/genética , Escoliosis/fisiopatología , Convulsiones/complicaciones , Convulsiones/epidemiología , Convulsiones/genética , Convulsiones/fisiopatología , Adulto JovenRESUMEN
Cyclin-dependent kinase-like 5 (CDKL5) is an X-linked gene encoding a serine-threonine kinase that is highly expressed in the central nervous system. Mutations in CDKL5 cause neurological and psychiatric symptoms, including early-onset seizures, motor dysfunction, autistic features and sleep breathing abnormalities in patients. It remains to be addressed whether loss of CDKL5 causes respiratory dysfunction in mice. Here, we examined the respiratory pattern of male Cdkl5-/y mice at 1-3 months of age during resting breathing and respiratory challenge (i.e., hypoxia and hypercapnia) via whole body plethysmography. The results demonstrated that the resting respiratory frequency and tidal volume of Cdkl5-/y mice was unaltered compared to that of WT mice at 1 month of age. However, these mutant mice exhibit transient reduction in tidal volume during respiratory challenge even the reduction was restored at 2 months of age. Notably, the sigh-breathing pattern was changed in Cdkl5-/y mice, showing a transient reduction in sigh volume at 1-2 month of age and long-term attenuation of peak expiratory airflow from 1 to 3 month of age. Therefore, loss of CDKL5 causes breathing deficiency, supporting a CDKL5-mediated regulation of respiratory function in mice.
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Proteínas Serina-Treonina Quinasas/deficiencia , Trastornos Respiratorios/genética , Factores de Edad , Animales , Peso Corporal/genética , Genotipo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pletismografía , Proteínas Serina-Treonina Quinasas/genética , Ventilación Pulmonar/genética , Trastornos Respiratorios/fisiopatología , Volumen de Ventilación Pulmonar/genéticaRESUMEN
The glycine receptor α3 subunit is known to be a target for cAMP/PKA-mediated phosphorylation and regulation. Mice that lack this subunit are apparently normal but the 5-HT1A-receptor mediated modulation of respiratory network activity is disturbed. Since the intracellular cAMP-concentration is reduced in mice that lack the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2) gene, we aimed to test if the α3 subunit of the glycine receptor is involved in the development of the breathing phenotype of MeCP2-deficient mice (Mecp2-/y). Therefore, we generated a double knock-out mouse line that lacks both the Mecp2 gene as well as the gene (Glra3) for the α3 subunit of the ionotropic glycine receptor. As compared to WT and Glra3-/- mice, both Mecp2-/y mice and Mecp2-/y; Glra3-/- mice (DKO) showed a slower respiratory rate and a tendency towards higher numbers of apneas. Interestingly, the irregularity of the breathing was significantly reduced in DKO as compared to Mecp2-/y littermates. In the light of the unaltered survival of DKO mice, however, the contribution of the glycine receptor α3 subunit for development and progression of the breathing disturbances in the mouse model of Rett syndrome appears to be only of minor relevance.
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Receptores de Glicina/metabolismo , Trastornos Respiratorios/etiología , Síndrome de Rett/complicaciones , Síndrome de Rett/genética , Animales , Modelos Animales de Enfermedad , Proteína 2 de Unión a Metil-CpG/deficiencia , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pletismografía , Receptores de Glicina/genética , Trastornos Respiratorios/genética , Síndrome de Rett/mortalidad , Análisis de SupervivenciaRESUMEN
In the study, 15 K. pneumoniae strains were isolated from the mink experiencing respiratory distress in mideastern Shandong province, China, and the prevalence of K. pneumoniae in the sampled mink was 11.9% (15/126). Fourteen (93.33%) of the 15 K. pneumoniae isolates were identified as serotype K2 and hypermucoviscosity phenotype. The 12 virulence-associated genes of the K. pneumoniae isolates were tested. The prevalence of the wabG gene for the isolates were 100% (15/15), the ureA gene 100% (15/15), the rmpA gene 93.33% (14/15), the aerobactin gene 93.33% (14/15), the uge gene 93.33% (14/15), the IucB gene 80% (12/15) and the ybtA gene 13.33% (2/15). But the other five genes, fim, iroNB, wcaG, alls and kfuBC, gave a negative PCR reaction in the 15 isolates, respectively. The animal experiments using K. pneumoniae-SD-12 and K. pneumoniae-SD-21 demonstrated that the serotype K2 was high virulence for mice and mink. These finding implied there exist potential threat that K. pneumoniae pathogens could transmit to human, especially the fur animal farm workers and residents lived near the fur animal farms. Therefore, the etiology and epidemiological surveillance of K. pneumoniae in mink should be strengthened for people's public health.
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Proteínas Bacterianas/metabolismo , Infecciones por Klebsiella/epidemiología , Klebsiella pneumoniae/patogenicidad , Absceso Hepático/epidemiología , Trastornos Respiratorios/epidemiología , Serogrupo , Factores de Virulencia/metabolismo , Animales , Proteínas Bacterianas/genética , China/epidemiología , Incidencia , Infecciones por Klebsiella/genética , Infecciones por Klebsiella/virología , Absceso Hepático/genética , Absceso Hepático/virología , Ratones , Visón , Fenotipo , Trastornos Respiratorios/genética , Trastornos Respiratorios/virología , Factores de Virulencia/genéticaRESUMEN
Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. Many RTT patients have breathing abnormalities, such as apnea and breathing irregularity, and respiratory infection is the most common cause of death in these individuals. Previous studies showed that MeCP2 is highly expressed in the lung, but its role in pulmonary function remains unknown. In this study, we found that MeCP2 deficiency affects pulmonary gene expression and structures. We also found that Mecp2-null mice, which also have breathing problems, often exhibit inflammatory lung injury. These injuries occurred in specific sites in the lung lobes. In addition, polarizable foreign materials were identified in the injured lungs of Mecp2-null mice. These results indicated that aspiration might be a cause of inflammatory lung injury in Mecp2-null mice. On the other hand, MeCP2 deficiency affected the expression of several neuromodulator genes in the lower brainstem. Among them, neuropeptide substance P (SP) immunostaining was reduced in Mecp2-null brainstem. These findings suggest that alteration of SP expression in brainstem may be involved in autonomic dysregulation, and may be one of the causes of aspiration in Mecp2-null mice.
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Proteína 2 de Unión a Metil-CpG/genética , Neumonía/genética , Trastornos Respiratorios/genética , Síndrome de Rett/genética , Animales , Tronco Encefálico/metabolismo , Femenino , Expresión Génica , Humanos , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Masculino , Proteína 2 de Unión a Metil-CpG/deficiencia , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía/mortalidad , Neumonía/fisiopatología , Respiración , Trastornos Respiratorios/mortalidad , Trastornos Respiratorios/fisiopatología , Síndrome de Rett/metabolismo , Síndrome de Rett/fisiopatología , Sustancia P/genética , Sustancia P/metabolismo , Tasa de SupervivenciaRESUMEN
INTRODUCTION: The imprinted DLK1-DIO3 locus at 14q32.1-32.31 holds biological significance in fetal development, whereby imprinting errors are causal to developmental disorders. Emerging evidence has implicated this locus in other diseases including cancer, highlighting the biological parallels between fetal organ and tumour development. Areas covered: Controlled regulation of gene expression from the imprinted DLK1-DIO3 locus at 14q32.1-32.31 is crucial for proper fetal development. Deregulation of locus gene expression due to imprinting errors has been mechanistically linked to the developmental disorders Kagami-Ogata Syndrome and Temple Syndrome. In adult tissues, deregulation of locus genes has been associated with multiple malignancies although the causal genetic mechanisms remain largely uncharacterised. Here, we summarize the genetic mechanisms underlying the developmental disorders that arise as a result of improper locus imprinting and the resulting developmental phenotypes, emphasizing both the coding and noncoding components of the locus. We further highlight biological parallels common to both fetal development and disease, with a specific focus on lung development, respiratory disease, and lung cancer. Expert commentary: Many commonalities between respiratory and developmental defects have emerged with respect to the 14q32 locus, emphasizing the importance of studying the effects of imprinting on gene regulation patterns at this locus in both biological settings.
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Desarrollo Fetal/genética , Impresión Genómica , Péptidos y Proteínas de Señalización Intercelular/genética , Yoduro Peroxidasa/genética , Proteínas de la Membrana/genética , Neoplasias/genética , Trastornos Respiratorios/genética , Disomía Uniparental/genética , Animales , Proteínas de Unión al Calcio , Cromosomas Humanos Par 14/genética , Humanos , FenotipoRESUMEN
NDST1 encodes an enzyme involved in the first steps in the synthesis of heparan sulfate chains, proteoglycans that are regulators found on the cell surface and in the extracellular matrix. Eight individuals homozygous for one of four family-specific missense mutations in the sulfotransferase domain of the enzyme have been described. They have intellectual disability. Some additionally had hypotonia, ataxia. seizures, and/or short stature, but none had history of respiratory problems. No humans with homozygous null mutations are known. ndst1b (orthologous to NDST1) morpholino knockdown in zebrafish (Danio rerio) causes delayed development, craniofacial cartilage abnormalities, shortened body and pectoral fin length. Ndst1 homozygous null mice have craniofacial abnormalities and die within the first 10 h of life of respiratory failure. We report a girl upon whom deep phenotyping, extensive genetic and biochemical investigations, and exome sequencing were performed. She had cranial nerves dysfunction, gastroesophageal reflux, history of a seizure, ataxia, developmental delays, head sparing failure to thrive, and minor malformations including distinctive facial features and a bifid uvula. Compound heterozygous mutations in NDST1 were identified, in the heparan sulfate N deacetylatase domain of one allele and the sulfotransferase domain of the other allele. This report expands the phenotypic spectrum of Ndst1 deficiency in humans. © 2017 Wiley Periodicals, Inc.